Cyclin D1: Mechanism and Consequence of Androgen Receptor Co-repressor Activity

Abstract

Androgen receptor regulation is pivotal for prostate growth and development. Activation of the receptor is dictated by association with androgen (ligand) and through interaction with co-activators and co-repressors. We have shown previously that cyclin D1 functions as a co-repressor to inhibit ligand-dependent androgen receptor activation. We demonstrate that cyclin D1 directly binds the N terminus of the androgen receptor and that this interaction is independent of ligand. Furthermore, we show that the interaction occurs in the nucleus and does not require the LXXLL motif of cyclin D1. Although two distinct transactivation domains exist in the N terminus (AF-1 and AF-5), the data shown support the hypothesis that cyclin D1 targets the AF-1 transactivation function. The constitutively active AF-5 domain was refractory to cyclin D1 inhibition. By contrast, cyclin D1 completely abolished androgen receptor activity, even in the presence of potent androgen receptor co-activators. This action of cyclin D1 at least partially required de-acetylase activity. Finally, we show that transient, ectopic expression of cyclin D1 results in reduced cell cycle progression in androgen-dependent LNCaP cells independent of CDK4 association. Collectively, our data support a model wherein cyclin D1 has a mitogenic (CDK4-dependent) function and an anti-mitogenic function (dependent on regulation of the AF-1 domain) that can collectively control the rate of androgendependent cellular proliferation. These findings provide insight into the non-cell cycle functions of cyclin D1 and provide the impetus to study its pleiotropic effects in androgen-dependent cells, especially prostatic adenocarcinomas.

Cyclin D1: polymorphism, aberrant splicing and cancer risk

“…Specifically, cyclin D1 has been shown to regulate a number of sequence-specific transcription factors, including C/EBPb (Lamb et al, 2003), STAT3 (Bienvenu et al, 2001), DMP1 (Inoue and Sherr, 1998), and BETA2/NeuroD (Ratineau et al, 2002). The largest class of transcription factors regulated by cyclin D1 belong to the nuclear receptor superfamily, and include the estrogen receptor (Zwijsen et al, 1998;Lamb et al, 2000), androgen receptor (Knudsen et al, 1999;Reutens et al, 2001;Petre et al, 2002;Burd et al, 2005), thyroid hormone receptor (Pibiri et al, 2001), and peroxisome proliferator activated receptor-g (Qin et al, 2003). In many cases cyclin D1 was shown to directly associate with the transcription factors, independent of CDK4 association, and modify transcription factor action through cell-cycle independent mechanisms.…”

Cyclin D3 action in androgen receptor regulation and prostate cancer

“…In specific cell types, cyclin D1 is found in association with the estrogen receptor a, thyroid hormone receptor, peroxisome proliferatoractivated receptor-g and the androgen receptor (AR) (Neuman et al, 1997;Zwijsen et al, 1998;Knudsen et al, 1999;Reutens et al, 2001;Lin et al, 2002;Petre et al, 2002;Petre-Draviam et al, 2003;Wang et al, 2003;Burd et al, 2005). With estrogen receptor, cyclin D1 can potentiate receptor activity independently of ligand and CDK4-kinase activity (Neuman et al, 1997), through formation of a ternary complex with estrogen receptor a and P/CAF, thereby altering chromatin structure to facilitate gene transcription (McMahon et al, 1999).…”

“…In prostatic cells, cyclin D1 associates with and inhibits AR function, independent of CDK4 activating function and the LxxLL motif (Knudsen et al, 1999;Petre et al, 2002;Burd et al, 2005). Mechanisms are attributed to a discrete repressor domain, which binds to the AR N-terminus and prevents ligand-dependent conformational changes in AR .…”

“…Mechanisms are attributed to a discrete repressor domain, which binds to the AR N-terminus and prevents ligand-dependent conformational changes in AR . Additionally, this motif can recruit histone deacetylase 3 (HDAC3), and the AR-repressor function of cyclin D1 is dependent on HDAC function (Lin et al, 2002;Petre et al, 2002;Petre-Draviam et al, 2005). Concordantly, the repressor domain of cyclin D1 is also required for cyclin D1-mediated suppression of peroxisome proliferator-activated receptor-g activity (Fu et al, 2005).…”

“…Concordantly, the repressor domain of cyclin D1 is also required for cyclin D1-mediated suppression of peroxisome proliferator-activated receptor-g activity (Fu et al, 2005). These observations led to the hypothesis that while androgen induction of cyclin D1 leads to CDK4 activation and promotes G1-S progression (Knudsen et al, 1998;Xu et al, 2006), accumulated cyclin D1 regulates this by binding to AR and suppressing subsequent signaling (Knudsen et al, 1999;Reutens et al, 2001;Petre et al, 2002). Recently, it was observed that this process is disrupted in PCa through alternative splicing of cyclin D1 (which compromises AR regulation), or through aberrant cyclin D1 expression (loss or cytoplasmic sequestration) (Burd et al, 2006;Comstock et al, 2007).…”